Studies have recently been performed about the iontophoresis using the electric driving force in order to enhance the absorption of drugs which have been introduced from the skin or mucosal membrane into the living body. The iontophoresis is a process comprising steps of applying a donor device having an electrode including a drug holding layer and a reference device pairing off with said donor device and having an electrode free from drug to the skin or mucosal membrane, and applying an electric current across the both electrodes, one of them forming an anode or another an cathode, so as to promote absorption of the drugs into the living body.
In contrast to the oral administration known as a general drug administration method, the iontophoresis is characterized in that it may be easy to administer a drug, maintain the concentration of the drug in the blood, and avoid any side effect of the drug on the digestive organs, and the iontophoresis system provided with the donor device, reference device, and a current-carrying device for energizing these devices have been studied eagerly and developed.
The relationship between the value of a supplied electric current and a dose at the time when a drug administration takes place using the conventional iontophoresis system will now be described with reference to FIG. 12.
FIG. 12 shows an equivalent circuit of identifying the skin electrically, where R1 designates an ohmic resistance, R2 a polarization resistance, and C a polarization capacity.
When a direct current or voltage/current having pulse wave-forms is applied between the donor and reference devices so as to energize the skin, the electric current will be allowed to pass through the ohmic resistance R1 and polarization resistance R2, and at the same time, an electric charge will be accumulated in the polarization capacity C. And then, if the electric charge of a predetermined quantity of electricity is accumulated in the polarization capacity C, most of the electric currents will pass through the ohmic resistance R1, and then, an electric current having a value substantially equal to that of the current as applied between the donor and reference devices will pass through the skin. At this time, since the current value present in the skin and the quantity of drug delivered to the skin (thereafter referred to as "drug delivery quantity") are directly proportional to each other, the drug delivery quantity can be predicted to some degree based on said electric value.
However, with the process for applying direct current or pulse wave form voltage/current, a complete charging of the polarization capacity C may cause the whole electric currents to concentrate on the ohmic resistance R1 so as to give an electric stimulus to the skin or mucosal membrane, whereby any supplied current value can not be raised to a higher level, with the consequential restriction laying down on the dose.
It would be possible that in the application of pulse wave-form voltage/current, electric charges as accumulated in the polarization capacity C during the suspension of voltage/current application are fully discharged with an exceedingly reduced ratio of the time for which the application of voltage/current is carried out for one pulse (thereafter referred to as pulse duty ratio); such a method will prolong the period of time required for drug administration, such that there had arisen a problem that the drugs applied may not work effectively.
In this connection, a variety of studies have been performed about the power supply, donor device, and reference device as well as the current-carrying method in order to reduce as much as possible electric stimulus which may be given to the skin or mucosal membrane, and to administer drugs efficiently and smoothly.
For example, published Japanese patent applications Nos.2-45461, 3-49589, and 4-1634 disclosed pulse depolarization-type current-carrying method as a current-carrying method in which electric charges which the polarization capacity C has been equipped with may be discharged actively. Such methods arrange within a current-carrying device a circuit forming a short-circuit between the donor and reference devices in such a manner that electric charges as accumulated in the polarization capacity C during a suspension of pulse application being made as per each pulse will be actively discharged (depolarized). Since such a depolarization may reset the equivalent circuit as shown in FIG. 12 into the state where no electric charge is stored within the polarization capacity C, in the next application of pulse waves, an electric current will pass through the ohmic resistance R1, polarization resistance R2, and polarization capacity C as well, thereby to lead to the decrease of chance of electric stimulus being given to the skin or mucosal membrane.
Then, a detection method for current value for determining the drug delivery quantity in a conventional pulse depolarization-type iontophoresis system will be described.
FIG. 13 is a view for the detection of current for use in a conventional constant current controlled pulse depolarization-type iontophoresis system.
Referring to FIG. 13, A1 and A2 identify an ammeter of measuring a current passing through the living body, and SW a switch for performing the pulse depolarization. As shown by this drawing, in this conventional pulse depolarization-type iontophoresis system, the ammeter is placed in the position labeled as A1 or A2 to measure electric current which passes through the living body at the time of application of pulse. That is, the value of current is a total of the value of a current (thereafter referred to as "load current value") passing through the ohmic resistance R1 and polarization resistance R2, and the current value of electric charges stored in the polarization capacity C, said total being identical to a current value to be applied (thereafter referred to as "applied current value"). Thus, the control of drug delivery quantity is achieved by the control of a current quantity passing through the living body in view of the applied current value which has been measured in the event of current.
Next, the structure of the donor device for use with the conventional iontophoresis system will be described.
FIG. 14 is a sectional view showing the components of a conventional donor device. In this drawing, 41 designates a donor device, 42 an electrode, 17 a drug holding layer, and 18 a lead wire.
As shown in FIG. 14, the conventional donor device 41 comprises the electrode 42 which affords a dynamic support to the drug holding layer 17 as well as applies to the drug holding layer 17 a voltage or current, the drug holding layer 17 formed by the drug holding member impregnated with a drug for supplying by means of a voltage or a current applied via an electrode 42 the drug to the skin or mucosal membrane abutted on the lower end face, and the lead wires 18 made of copper, gold, platina, sliver, etc., for supplying to the electrode 42 an electric current from the current-carrying device.
The electrode 42 is roughly divided into a polarizable electrode of generating polarization therewithin at the application of voltage, as is often the case with platina, gold, carbon, titan etc., and an unpolarizable electrode where no polarization occurs at the application of voltage, like silver, silver chloride, copper, copper chloride etc.
The polarizable electrode is low in energy efficiency because the voltage drop due to the polarization acts to lower the substantial voltage for transmission or delivery of drugs. In addition, the polarization tends to bring about a change of pH of solution in the drug holding layer adjacent to the electrode to such an extent that the drug may change its nature, thereby to cause a reduction in the medicinal effectiveness or a stimulus given to the skin. In the view of such problems, there is a trend toward frequent application of the unpolarizable electrode.
On the other hand, the following studies are also taking place about the donor device using the unpolarizable electrode in order that drugs may be introduced into the living body more effectively.
For example, Japanese Patent Laid-Open No.63-102768 (thereafter referred to as "publication A") disclosed "a donor device including a moisture restoring layer interposed between an electrode and a drug-containing layer and a sealing cover provided outside the electrode", reciting that a sufficient restoring of moisture in the drug-containing layer during the current passing will enable an effective percutaneous absorption.
Additionally, Japanese Patent Laid-Open No.63-502404 (thereafter referred to as "publication B") disclosed "a donor device having a first storing member for containing electrolytes, a second-storing member adjacent to said first storing member for containing effective components, and an ion exchange membrane serving as a preventive member against ion emigration for preventing any possible pass between the first and second storing members of ions having an electric charge equivalent to that of at least partially ionized components", with a description that such an arrangement can improve the rate and efficiency at which drugs may be delivered to the affected site, and that prevention may be possible of skin traumas including a chemical burn caused by uncontrollable production between the donor and reference devices of protons or hydroxide ions, and an electric burn caused by the use of a high electric current.
Furthermore, WO No.95/00200 (thereafter referred to as "publication C") disclosed a donor device containing a conductive solution between a reversible electrode and a drug holding means, indicating that avoidance can be made of any decrease in the transport number of ionized drugs due to various kinds of ions which have been liberated from the reversible electrode during the current passing, and that the delivery efficiency of ionized drugs into the body may be improved.
Above-mentioned conventional iontophoresis system and the current-supplying method therefor, however, had the following problems.
1) The ohmic resistance R1, polarization resistance R2, and polarization capacity C in the equivalent circuit as shown in FIG. 12 vary in their values with individuals to be furnished with a drug, and it is difficult to accurately estimate the drug delivery quantity from an applied current value on the grounds that even though using the same takes place with one and the same applied current values, the current value substantially involved in the drug administration may change according to each individual. Consequently, even in the case of the same applied current value used, there may occur variation in the delivered quantity of a drug that is absorbed into the respective individual, which may give rise to a loss of reliability.
2) If the iontophoretic treatment is conducted at regular intervals, eventual accumulation of the variations in the drug delivery quantity as recited in the article 1 is likely to make a difference between the drug delivery quantity and therapeutic effect, which is problematic in that the therapeutic reliability may be lost.
3) Administration of a drug having its therapeutic range and toxic range of the concentration thereof in blood which stand close to each other (a narrow therapeutic window) must be carried out with the greatest care because there is no correct grasping of the drug delivery quantity as indicated in the article 1, and moreover, in some cases, it is inevitable that the dose can not help but be restricted.
4) When the unpolarizable electrode is used in the donor device, ions that have eluted from the unpolarizable electrode to the drug holding layer during the current passing hinder the transfer of a drug so as to lower its transport number, and decrease the drug movement amount toward the target site, thus resulting in reduction of medicinal efficiency.
5) There lies a problem in publication A that since ions eluted from the unpolarizable electrode diffuse within the moisture restoring layer before they reach the drug-containing layer, there may be a reduction of medicinal effect as in the article 4.
6) There lies a problem in publications B and C that though the ion exchange membrane acts to prevent ions eluted out of the electrode from traveling to the layer for containing drugs, the electrolytes contained in the first storing member and the conductive solution adversely affect the absorption of drugs into the skin in such a fashion that the required medicinal effect can not sufficiently be achieved.
The present invention is, for the solution of the above mentioned conventional tasks, to provide an iontophoresis system which is simple in structure, and excellent in medicinal effect, safety, reliability, and productivity, wherein variation in the drug delivery quantity due to the individual differences in the impedance of skin and mucosal membrane may be decreased, the reduction of drug delivery quantity due to the elution of ions from the unpolarizable electrode in the donor device may be avoided, and a constant quantity of drugs may be smoothly delivered into the living body with high efficiencies of delivery and energy; and a control process for current of an iontophoresis system having an excellent medicinal effect, wherein the influence of the individual difference in the impedance of skin or mucosal membrane may be decreased to smoothly deliver a constant quantity of physiologically activated substances into the living body.